Acute neurologic disorders such as stroke and head trauma are presently untreatable. Recent breakthroughs in the understanding of how neural tissue degenerates, post-ischemia, have made possible several avenues of therapeutic intervention for these devastating disorders which hold the promise of salvaging much of the brain tissue that is destroyed in the hours following stroke or head trauma. It has been shown that excitatory amino acid (EAA) neurotransmitters, Glutamate and aspartate are over released after a stroke and that this actually stimulates nerve cells to death. This process is called excitotoxicity and has lead to the development of EAA receptor blockers as a therapeutic strategy. These agents, although effective, have proven to have unacceptable side effects. The Regentech approach is to inhibit the release of EAAs presynaptically via blocking the n-type calcium channel that regulates EAA release. We have identified a group of agents that acts at n-type channels. Phase I - we will demonstrate efficacy of these agents in an in vitro and in vivo model system of neuroprotection. An attempt to obtain some structure activity relationships will also be made. Phase II - We will launch a medicinal chemistry effort to derivatize the agent characterized in phase I. The goals here are to generate agents with greater potency at the n-type calcium channel.